Even though some will claim the chewing of gum and gum-like substances is as old as ancient Egyptian civilization, use, as a way of delivering therapy didn’t become a buzz till nicotine gums were introduced in the 1980s.

Ever since, the manufacture and development of functional or medicated chewing gum (MCG) have been steadily gaining momentum and it’s now an accepted oral delivery format.

MCGs are solid oral preparation that’s intended to be chewed for a certain period to effectively deliver the drug, after which the gum mass is discarded, not swallowed. Since the chewing habit of most consumers is relatively long enough to continuously release the drug in the oral cavity, MCGs act as an effective extended-release dosage form.

Drugs released while chewing can either be absorbed directly into the bloodstream via the buccal membrane or it could be swallowed with saliva and absorbed in the gastrointestinal (GI) tract. The drug concentration that’s absorbed via the GI tract is subjected to the first-pass metabolism unlike those that will be absorbed in the oral cavity. The first-pass metabolism reduces the amount of drug that’s eventually absorbed which normally affects the administered dosage.

However, since the majority of absorption takes place in the mouth before the drug is swallowed, most of the administered drug reaches the system. Also, the chewing process dissolves the drug in the saliva quickening absorption in the GI. As most of the given drug in MCGs gets absorbed, a reduced dose may be required, lowering the chances of side effects.

Unlike other oral dosage forms, MCGs offer a discrete and convenient way of administering medications, greatly encouraging compliance.

The formulation of drugs like pain-relieving substances, antiemetics, antifungals, vitamins, nicotine as chewing gum has broadened the dosage format application and admission into the marketplace.

This oral delivery system however remains relatively new and non-mainstream may be due to its “unconventionality” but also because more autonomous scientific studies are needed to back up existing claims.

It’s been decades since the first nicotine gum was introduced, yet the number of medications that have found their way into chewing gum is still somewhat low. Suitability of formulation process and stability of the drug in the dosage form plays a major role in these limitations.

To increase acceptance and promote the widespread use of MCGs, many innovative concepts are emerging with more in the works. A prominent one is the incorporation of more than one drug in single dosage formulations which can effectively reduce polypharmacy, encouraging patient compliance.

Also, separation of drug components with different release times as in modified release is possible in certain MCGs. More on this will be discussed later in the article.

This article aims to provide a general overview of MCGs exploring the benefits, disadvantages, and clinical role in oral drug delivery.

Advantages and therapeutic benefits of MCGs
Medicated chewing gum has a rapid onset of action and high bioavailability, making it very effective compared to other oral delivery systems. In addition, MCGs can be used to achieve both local and systemic action. Local drug effects are produced in the mouth while systemic effects can be achieved when drugs are swallowed or absorbed in the oral mucosa. Drugs absorbed via oral mucosa act faster as oral veins drain into the vena cava which takes the drug straight into the systemic circulation.

Another advantage of MCG is that it is a very discrete format that can be used anywhere and anytime, not requiring water for use. Product stability is good because the incorporated drug is protected from light, oxygen, and moisture. Also, MCG is well accepted among children and teenagers, which is great as compliance is an issue in this age group.

Mastication and flavor-induced excitement of the gustatory system that stimulates saliva production while chewing is also a positive therapeutic benefit of MCG. The increased saliva flow combats dry mouth (xerostomia), strengthening its protective properties. It also provides an easy way of giving drugs orally to people with pain and difficulty swallowing especially following a surgical procedure.

Certain drugs such as acetylsalicylic acid, dimenhydrinate, and caffeine show a faster rate of absorption with MCG than tablets. Also, it’s worth mentioning MCG offers fewer side effects and a reduced risk of overdose as drug delivery can be terminated anytime by discarding the gum.

Chewing gum also improves blood flow to the brain, stimulating alertness and improving focus and work performance. In addition to being perfect for self-medication, especially in acute illness, MCGs provide a reduced risk of gastric intolerance as the saliva delivers the drug fractionally and continuously. Hence, the stomach is spared from direct contact with large concentrations of drugs.

The downside of MCGs as a drug delivery system
Like all drug delivery systems, there are downsides of MCGs. For one, the drug dissolved in saliva disappears rapidly from the oral cavity following involuntary swallowing and saliva dilution. This could shorten the duration of action for local drug delivery, especially in extended-release formulations. Also, drug release from the dosage form is strongly influenced by consumers’ chewing habits which can vary significantly among different age and ethnic groups.

The time of administration also might be cut short unexpectedly as the presence of the delivery system in the oral cavity interrupts speaking, drinking, and eating. In addition, the presence of sugar in certain MCGs leads to the production of metabolic acid in dental plaque, causing caries and other oral health problems. At the same time, MCGs are not exactly the oral delivery system of choice in under-aged children as there’s the concern of swallowing and choking.

Also, regular and constant use of MCGs can stress the jaw, affecting the temporomandibular joint and masseter. Lately, the presence of sorbitol in certain MCG formulations may cause flatulence and diarrhea, while constant swallowing of saliva can cause stomach irritation, aches, and gastric ulcer.

Factors affecting drug release from MCGs
A major concern in MCG formulation is controlling how incorporated drugs are released into the body. For this, the complete release of drugs from the delivery system is highly desired for optimum effect.
There are three major determining factors here:

1. Consumer-related: Individuals have different chewing habits which affect how quickly and how much drug is released. Characteristics such as speed, intensity, duration, and frequency of chewing are of great interest here. It goes without saying, the faster and harder a user chews, the more readily the drug is released. The European Pharmacopoeia recommends 60 chews/min for adequate drug release.
2. Process-related: formulation process and composition of MCGs also play a major role. Mixing of active ingredients with hydrophilic or hydrophobic compounds is employed in drug formulation to modify drug release.
3. Drug-related: drugs with high aqueous solubility are readily soluble in saliva, releasing rapidly and completely from MCG into the oral cavity. While lipid-soluble and slightly water-soluble drugs are released more slowly as they are first released into the gum base then saliva.

Controlling drug release from MCGs
Since most drugs are lipophilic, their release from MCGs formulation is slow and incomplete. To increase the rate and extent of the release, certain techniques can be employed during formulation, such as:

• Coating of drug with hydrophilic gum;
• Encapsulation of active ingredient;
• Addition of buffering agent;
• Use of solubilizing agent; and
• Incorporation of the drug into gum base by solid dispersion.

Some methods can also be used to reduce the release rate in highly hydrophilic drugs with a rapid release. After all faster release doesn’t guarantee a more complete release of the drug. Some MCGs with slower release profiles show more complete drug release. A sustained release can be attempted by:

• Coating of drug with a hydrophobic compound;
• Binding of the drug to an ion exchange resin; and
• Reduction of drug particle size.

Type of MCGs
There are two major types of MCGs based on differences in the formulation process: 1) Extruded gum and 2) compressed bi-layered gum.

Extruded gum
These types of MCGs are produced using a traditional method of formulation that involves intensive mixing and elevated temperature to achieve a continuous matrix. This allows the active ingredient to be uniformly dispersed in the gum base forming a homogeneous mix. The final product surface is usually sprayed with coating agents to form a coated layer.

Drug release from extruded gum is not as fast as compressed gum because the drug components are tightly bound to the gum base and not freely released. For fat-soluble actives that are not readily released on chewing, extruded gum making might be unfit. Vitaball—producers of vitamin-enriched gums—addressed this problem by adding such fat solubles in the gum coating, instead of gum matrix where they can get lost in. This is helpful because gum coating is usually the first to break on chewing releasing drugs within the first few chews.

This traditional way of making chewing gums however limits the number of active ingredients that can be produced this way as certain substances are heat-sensitive.

Also, shelf life and product stability over a long period are questionable as there is the risk of possible interaction between active ingredients and other gum ingredients.

Compressed bi-layered gum
In this type of MCG, ingredients are effectively separated into separate layers, two in bi-layered gums. With this innovation, the same or different active ingredients can be effectively separated in chewing gum to have different release times, with absorption occurring in various regions from the mouth to the GI tract.

The release of fat solubles is also not a problem as the active ingredient is separated from the gum base. A good example is by Fertin Pharma, a private label gum maker. They produce bi-layered compressed chewing gum containing a gum layer and a thin mint layer. Fat-soluble ingredients are added to the mint layer that dissolves immediately on chewing, releasing the drug quickly.
Bi-layered gum can also be used to achieve extended-release by adding drugs to the gum layer where it will be slowly released during the entire chewing period.

What’s more? The direct compression method of making bi-layered gums is a cool and dry process suitable for a wide range of ingredients including biologics. Formulation involves gentle mixing of ingredients at a solid-state then direct compression to form gum tablets.

Various applications of MCGs
Oral health care
Drug delivery from MCGs takes place in the oral cavity, making it the perfect format for the treatment and prevention of oral diseases.
It can be used to achieve local therapy from the controlled release of active ingredients over an extended period. The chewing of sugar-free gum stimulates saliva flow which elevates plaque pH thereby reducing the occurrence of dental caries. Specific examples include:

1. Fluoride chewing gum (Flourette): used for the prevention of dental caries by remineralization. This is most applicable in children living in areas with low fluoride concentration in drinking water and adults with xerostomia.
2. Chlorhexidine chewing gum (Vitaflo CHX): used for inhibiting plaque growth and treatment of gingivitis, periodontitis, oral and pharyngeal infection. The advantage of chlorhexidine chewing gum over the mouth rinse formulation includes better taste masking and less chance of staining teeth.
3. Antibacterial and antifungal chewing gum: used for the treatment of fungal and bacterial infection of the oral cavity and adjacent regions. E.g sulphonamide containing MCG for bacterial infection while those containing miconazole, nystatin can be used for fungal infections like candidiasis. The formulation is quite convenient with few side effects as their effect is mostly local.

Smoking cessation
Chewing gum formulations containing nicotine (Nicorette), silver acetate, lobeline have been studied and found to be effective in smoking cessation. Nicotine chewing gum is superior to the other drugs as an effective nicotine replacement therapy for breaking the smoking habit.

Pain management
MCGs containing acetylsalicylic acid (Aspergum) are effective for managing mild, acute pain, headaches, muscular aches, etc. While those containing methadone are more effective for acute, strong pain.
The quick action of chewing gum formulation provides rapid pain relief making it suitable for acute pain management.

Anxiety and depression management
MCGs containing psychoactive substances like cannabinoids (e.g. CanChew) are useful in reducing symptoms of depression and anxiety. Other known benefits of cannabinoid chewing gum include chronic pain relief, reduction of cancer-related symptoms (nausea, vomiting, pain).

GI-related conditions
Antacid chewing gums such as those containing calcium carbonate (Chooz) neutralizes stomach and esophageal acidity relieving indigestion and heartburn symptoms.
Antacid chewing gum is superior to the chewable antacid tablet because it provides prompt relief, sustaining the effect over a longer period.

Basic nutrients supplement
MCGs containing multivitamins (e.g Vitaball) are useful especially in children for normal metabolic functioning, wound healing, immunity, bone development. This is a convenient alternative to chewable tablets which have aftertaste children dislike.

CNS stimulation
MCGs containing psychoactive substances like caffeine (Stay Alert) are used to increase energy and alertness. Unlike other available caffeine products, the caffeine chewing gum effect occurs faster and is more prominent.
There’s less risk of overdose and misuse of the stimulant as the dose is gradually delivered by chewing gum which can last a while.

Motion sickness
Dimenhydrinate chewing gum (Travvell) is used for the treatment and management of travel illness.
Other available MCGs active ingredient include:

1. Xylitol for treatment of otitis media.
2. Guarana used in obesity management.
3. Chromium used in dieting.

At this point, the unique role of functional chewing gums in oral drug delivery is clear as day. And it’s a safe bet to assume this unconventional oral delivery format will be a huge part of redefining drug therapy soon.

With time and technological advancement, more sophisticated MCGs with smart functionality will be introduced. One thing is for certain though, MCG as an alternate oral delivery system is continuously evolving and here to stay. 

References

1. Aslani A, Rostami F. Medicated chewing gum, a novel drug delivery system. J Res Med Sci. 2015 Apr; 20(4): 403–411. [PMC free article]
2. Khatun S, Sutradhar KB. Medicated chewing gum: An unconventional drug delivery system. Int Curr Pharm J. 2012;1:86–91. [Google Scholar]
3. Asija R, Patel S, Asija S. Oral dosages forms: Medicine containing chewing gum: A review. J Drug Delivery Ther. 2012;2:90–5. [Google Scholar]
4. Surana AS. Chewing gum: A friendly oral mucosal drug delivery system. Int J Pharm Sci Rev Res. 2010;4:68–71. [Google Scholar]

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Rukayat Adedeji is a Pharma Copywriter who specializes in writing white papers, case studies, and research-driven articles for the pharmaceutical, nutraceutical, and biotech industry. She works primarily with CMOs and CDMOs in this field where she helps plan, research, create, and publish relevant marketing content. Visit Adedeji’s official site to learn more about her work and you can connect with her on LinkedIn here.